Posaconazole (CAS Registration No: 171228-49-2; CAS name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[1-(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy[methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is used for preventing and treating invasive fungal infections, such as those which are drug resistant or to which other medicines are ineffective, and the structure thereof is as follows:
One important intermediate for preparing posaconazole is a compound of formula IX,
wherein Q is substituted or unsubstituted phenylsulfonyl, p-tosylsulfonyl, p-chlorophenylsulfonyl or the like. U.S. Pat. No. 5,403,937A reported the synthesis of this intermediate (FIG. 1),
characterized in that, compound (2), obtained by reacting acid (1) with R-4-benzyl oxazolidone as a chiral auxiliary, is subjected to an asymmetric hydroxy-methylenation with triformol mediated by triethylamine and titanium tetrachloride to obtain compound (3), the compound (3) is then subjected to an intra-molecular iodization and etherification reaction to stereoselectively obtain tetrahydrofuran intermediate (4) (with a cis/trans molar ratio of 85:15 to 95:5), which is then reduced by lithium borohydride to remove the chiral auxiliary to obtain iodohydrin intermediate (5). The intermediates in all steps of the process are oily materials. In particular, an excess amount of iodine is required in the step of the intra-molecular iodo-ether cyclization, which is expensive and highly toxic. Furthermore, for removing the chiral auxiliary with lithium borohydride, not only the reagent is expensive, but also the iodohydrin intermediate (5) obtained after reduction is required to be separated from the chiral auxiliary by column chromatography, unfavorable for industrial production.
WO2013042138 reported another synthesis method of a compound of formula X (FIG. 2),
characterized in that, R-4-phenyl oxazolidone is used as a chiral auxiliary, and the auxiliary is removed by hydrolyzing with sodium hydroxide and hydrogen peroxide. Although this route avoids separating the obtained iodo acid intermediate (formula-7) and the chiral auxiliary by a column chromatography, it is still required to use an excess amount of iodine in the step of preparing the compound of formula-6 by iodization and cyclization, which confronts with the same problem as the above patent application. Furthermore, because hydrogen peroxide is required to be used in the step of removing the auxiliary by hydrolyzing with sodium hydroxide, there is a risk in industrial production.